Project Summary/Abstract Ketosis-prone diabetes mellitus (KPDM) affects ~20-50% of African American patients with newly diagnosed diabetes who present with diabetic ketoacidosis (DKA). At presentation of DKA, these patients have a severe decompensation in insulin secretion (beta-cell function) accompanied by severe insulin resistance. Unlike patients with type 1 diabetes, following intensive insulin treatment, many of these patients exhibit improvements in insulin secretion and insulin sensitivity and are able to discontinue insulin therapy (near- normoglycemia remission, HbA1c < 7%). The period of near-normoglycemia remission is variable and many patients eventually experience a hyperglycemic relapse or even DKA. Therefore, studying the underlying mechanisms leading to changes in insulin secretion and sensitivity and near-normoglycemia remission has implications for a significant number of African American patients with diabetes. DNA methylation and gene expression, have been proposed as mechanisms that affect insulin secretion and insulin sensitivity. In this proposal, based on preliminary results, the PI Priyathama Vellanki, MD, will test whether longitudinal gene expression and DNA methylation changes in specific pathways affect quantitative traits of insulin sensitivity and secretion along with achievement and maintenance of near-normoglycemia remission. In Aim1, she will characterize whether gene expression and DNA methylation changes in glucose sensing and insulin secretion pathways associate with quantitative measures of insulin secretion derived from glucagon stimulation tests. In Aim 2, she will characterize glucose uptake and insulin signaling pathways with quantitative traits of insulin sensitivity from frequently-sampled IV glucose tolerance tests (FSIVGTT). She will also test whether gene expression and methylation in these pathways associate with short- and long-term near-normoglycemia remission. Further, in order to develop blood-based biomarkers, she will test whether gene expression and DNA methylation in muscle correlate with those in blood. Successful completion of these aims will yield important insights into mechanisms that underlie changes in insulin sensitivity and secretion through the clinical course of patients with KPDM. The proposed aims will be performed under the guidance of an expert interdisciplinary mentorship team led by her lead mentor Dr. Umpierrez (expertise in KPDM) and co-mentor Dr. Alicia K. Smith (expert in epigenetics) along with an advisory committee comprised of experts in statistical genetics (Dr. Karen Conneely) and computational biology (Dr. Darko Stefanovski). Emory University is a world-class institution that has adequate and ample resources necessary to carry out the research aims, including the Georgia Clinical and Translation Science Alliance. Her structured training plan has formal didactic training at Emory along with hand-on training in performance of phenotyping studies and data analyses. The proposal along with the structured career development plan will poise Dr. Vellanki to become a successful independent NIH-funded clinical investigator.